DK149957B - METHOD OF ANALOGUE FOR THE PREPARATION OF S-ADENOSYL-METHIONINE ESTERS - Google Patents
METHOD OF ANALOGUE FOR THE PREPARATION OF S-ADENOSYL-METHIONINE ESTERS Download PDFInfo
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Abstract
Description
i 149957in 149957
Den foreliggende opfindelse angår en analogi fremgangsmåde til fremstilling af hidtil ukendte S-adenosylmethionin-e-stere med den nedenfor angivne formel II, og fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav l's kende-5 tegnende del anførte.The present invention relates to an analogous process for the preparation of novel S-adenosylmethionine esters of the formula II given below, and the process of the invention is characterized by the characterizing part of claim 1.
S-adenosylmethionin (SAM) vides at være en forbindelse, som er tilstede i alle levende organismer, og som deltager i et stort antal biologiske processer af fundamental betydning, eftersom SAM er den væsentlige donor for methylgrupper i or-10 ganismen.S-adenosylmethionine (SAM) is known to be a compound present in all living organisms and participates in a large number of biological processes of fundamental importance since SAM is the major donor of methyl groups in the organism.
Det vides ligeledes, at SAM indtil 1975 ikke har haft nogen praktisk anvendelse på grund af den extreme instabilitet.It is also known that until 1975 SAM did not have any practical application due to the extreme instability.
Fra og med 1975 har der været offentliggjort et antal patentskrifter (USA patentskrifterne nr. 3 893 999, 3 954 726 15 og 4 057 686) med relation til bestemte SAM-salte, som gan ske uventet har vist stabilitetskarakteristika, der gør det muligt at fremstille farmaceutiske formuleringer til anvendelse inden for adskillige områder af den humane terapi.As of 1975, a number of patent documents (United States Patent Nos. 3,893,999, 3,954,726,15 and 4,057,686) have been published relating to certain SAM salts, which may have unexpectedly shown stability characteristics which allow prepare pharmaceutical formulations for use in several fields of human therapy.
Selv om man således har afklaret et af de negative aspekter 20 ved SAM, har disse salte imidlertid stadig ikke løst det an det problem, som er forbundet med dette produkt, nemlig dets lave kapacitet med hensyn til passage igennem cellebarrierer, som medfører, at organismen har vanskeligt ved at absorbere forbindelsen, i særdeledhed når denne indgives oralt.Thus, although one of the negative aspects of SAM has been clarified, these salts still have not solved the problem associated with this product, namely its low capacity for passage through cell barriers, which causes the organism has difficulty absorbing the compound, especially when administered orally.
25 Med den foreliggende opfindelse er der nu tilvejebragt en analogi fremgangsmåde til fremstilling af en hidtil ukendt klasse af forbindelser, som har den nedenfor viste almene formel II, og disse forbindelser har overraskende vist sig at besidde en lige så høj grad af farmakologisk virkning 30 som den, der er kendt fra SAM-saltene, og at besidde en lige så stor eller større stabilitet, også ved forhøjede temperaturer, samt en større biotilgængelighed.With the present invention, there is now provided an analogous process for the preparation of a novel class of compounds having the general formula II shown below, and these compounds have surprisingly been found to possess an equally high pharmacological effect 30 as that known from the SAM salts, and to possess an equal or greater stability, even at elevated temperatures, as well as a greater bioavailability.
2 Ϊ499572 Ϊ49957
Ikke mindst dette sidste kendetegn gør det muligt at fremstille farmaceutiske formuleringer til oral anvendelse, som er særdeles værdifulde inden for den humane terapi.Not least, this last feature makes it possible to prepare pharmaceutical formulations for oral use which are extremely valuable in human therapy.
De omhandlede estere har den almene formel (II) 5 hvori R er en lineær eller forgrenet alifatisk gruppe med 1-6 carbonatomer, A- er en ækvivalent af en generisk anion af en stærk uorganisk eller organisk syre med en pK-værdi på under 2,5, m er 1, og 10 n kan variere fra 0-4, idet n fortrinsvis er 3.The esters of this invention have the general formula (II) wherein R is a linear or branched aliphatic group of 1-6 carbon atoms, A- is the equivalent of a generic anion of a strong inorganic or organic acid having a pK value of less than 2 , 5, m is 1, and 10 n may range from 0-4, with n preferably 3.
Det har også vist sig, at stabiliteten af de hidtil ukendte forbindelser med formel II påvirkes væsentligt af antallet af syreækvivalenter, som er bundet til hvert molekyle. Nærmere bestemt gælder det, at den maksimale 15 stabilitet opnås, når n er 3.It has also been found that the stability of the novel compounds of formula II is significantly affected by the number of acid equivalents attached to each molecule. More specifically, the maximum stability is obtained when n is 3.
U9957 3 I den efterfølgende tabel 1 er anført stabilitetsdata, sammenlignet med SAM, for visse estere med formel II i vandig opløsning ved 100 °C for forskellige pH-værdi-er, idet n overalt er 3.U9957 3 The following Table 1 shows stability data, compared to SAM, for certain esters of formula II in aqueous solution at 100 ° C for different pH values, with n being everywhere 3.
5 TABEL 1 pH i op- Tempera- % dekomponering efter R løsningen tur 15 min 30 min 60 min 240 min H 2 100 °C 80 lbO 100 100 H 3 100 °C 90 100 100 100 10 H 4 100 °C 100 100 100 100 CH3 2 100 °C 5 10 21 75 CH3 3 100 °C 6 13 25 100 CH3 4 100 °C 8 18 40 100 C2H5 2 100 °C 2 4 8 35 15 C2H5 3 100 °C 3 6 13 55 C2H5 4 100 °C 5 9 19 80 C4Hg 2 100 °C 2 4 8 30 C4Hg 3 100 °C 3 6 12 52 C4Hg 4 100 °C 4 9 17 75 20 Esterne med formel II er stabile i ubegrænsede tidsrum i tør tilstand ved 45 °C.5 TABLE 1 pH in up-% decomposition after the R solution turn 15 min 30 min 60 min 240 min H 2 100 ° C 80 lbO 100 100 H 3 100 ° C 90 100 100 100 10 H 4 100 ° C 100 100 100 100 CH3 2 100 ° C 5 10 21 75 CH3 3 100 ° C 6 13 25 100 CH3 4 100 ° C 8 18 40 100 C2H5 2 100 ° C 2 4 8 35 15 C2H5 3 100 ° C 3 6 13 55 C2H5 4 100 ° C 5 9 19 80 C4Hg 2 100 ° C 2 4 8 30 C4Hg 3 100 ° C 3 6 12 52 C4Hg 4 100 ° C 4 9 17 75 20 The esters of formula II are stable for an unlimited period in the dry state at 45 ° C .
Som indledningsvis anført udmærker de hidtil ukendte estere med formel II sig ved det overordentligt nyttige aspekt, der ligger i deres evne til at kunne passere igen-25 nem cellebarierer.As noted initially, the novel esters of formula II are distinguished by the extremely useful aspect inherent in their ability to pass through cell barriers.
De i tabel 2 angivne værdier påpeger dette vigtige træk ved de nye produkter.The values given in Table 2 point to this important feature of the new products.
U9957 4 I det første forsøg, der er kendt som "intestinale sække" (in situ), blev 2 mg af hvert produkt, der skulle afprøves, sammen med 1 ml af en fysiologisk opløsning anbragt i intestinale sække tilvejebragt i rotter under etherbedøvelse.U9957 4 In the first trial, known as "intestinal sacs" (in situ), 2 mg of each product to be tested, together with 1 ml of a physiological solution, was placed in intestinal sacs provided in rats under ether anesthesia.
5 Rotterne blev dræbt efter 2 timers forløb, og residualind- holdet af sækken (omgivende væg + indhold) blev analyseret.The rats were killed after 2 hours and the residual contents of the sac (surrounding wall + contents) were analyzed.
I det andet forsøg anvendtes tarmdele, hvis inderside var vendt udefter, inkuberet ved 37 °C i overensstemmelse med Krebs Ringer overfor en ekstern produktkoncentration på 10 10'4 M.In the second experiment, intestinal parts, the inside of which was facing outwards, were used incubated at 37 ° C according to Krebs Ringer opposite to an external product concentration of 10 10'4 M.
Produkterne blev alle behandlet med I^SO^ til opnåelse af salte, hvori n er 3.The products were all treated with 10 SO 2 to obtain salts wherein n is 3.
TABEL 2TABLE 2
Produktabsorption 15 Afprøvet tarme med indersiden i sække udad R λ af dosis nmol/h/mg væg H 5 0,009Product Absorption 15 Tested intestine with inner sacs outward R λ of dose nmol / h / mg wall H 5 0.009
Ch3 55 0,078 20 C2H5 59 0,061 C3H? 61 0,045 C4H9 65 0,037 C5Hi;l 68 0,025 C6H13 67 0,023 25 De omhandlede SAM-estere kan fremstilles ud fra et vil kårligt SAM-salt fremstillet ved kendte metoder. Fortrinsvis anvender man sulfatsaltet.Ch3 55 0.078 20 C2H5 59 0.061 C3H? 61 0.045 C4H9 65 0.037 C5Hi; 1 68 0.025 C6H13 67 0.023 The present SAM esters can be prepared from a well-known SAM salt prepared by known methods. The sulphate salt is preferably used.
Man fremstiller en opløsning med en koncentration på mellem 1 og 3?ό (fortrinsvis 2%) af koncentreret svovlsyre i den 5 149967 vandfrie alkohol, hvormed syren skal forestre SAM.A solution having a concentration of between 1 and 3? (Preferably 2%) of concentrated sulfuric acid is prepared in the anhydrous alcohol by which the acid must esterify SAM.
Til denne opløsning sætter man under omrøring en tilstrækkelig mængde SAM-sulfat til at opnå en slutkoncentration af SAM-ioner på mellem 10 og 100 g/1, fortrinsvis 50 g/1.To this solution, a sufficient amount of SAM sulfate is added, with stirring, to obtain a final concentration of SAM ions of between 10 and 100 g / l, preferably 50 g / l.
5 Når man anvender en alkohol med en lav molekylvægt, opnår man en klar opløsning, hvorimod man opnår en suspension, når man anvender en alkohol med en høj molekylvægt.5 When using a low molecular weight alcohol, a clear solution is obtained, whereas a suspension is obtained when using a high molecular weight alcohol.
I afhængighed af den anvendte alkohol opvarmer man under tilbagesvaling i 10 - 20 timer. Når reaktionen er forløbet 10 til ende, opnår man i alle tilfælde en klar opløsning.Depending on the alcohol used, it is heated at reflux for 10 - 20 hours. When the reaction is completed 10, a clear solution is obtained in all cases.
Foruden SAM-esteren indeholder den afsluttende reaktions-blanding små tiloversblevne mængder af SAM (op til et maksimum på 5¾) og produkter af SAM, der er fremkommet ved termisk nedbrydning, i variable mængder i overensstem-15 melse med den anvendte alkohol.In addition to the SAM ester, the final reaction mixture contains small residual amounts of SAM (up to a maximum of 5¾) and products of SAM resulting from thermal decomposition in variable amounts in accordance with the alcohol used.
Forholdene går fra en esteromdannelse på 80¾ og en mængde af nedbrydningsprodukter på 20°ό, når der er tale om en methylester, til en omdannelse på 50¾ og en mængde af nedbrydningsprodukter på 50?i, når der er tale om alkoholer 20 med 5-6 carbonatomer.The ratios range from an ester conversion of 80¾ and an amount of degradation products of 20 ° ό in the case of a methyl ester to a conversion of 50¾ and an amount of degradation products of 50? In the case of alcohols 20 by 5 6 carbon atoms.
Reaktionsblandingen afkøles, og man tilsætter en tilsvarende mængde t^O (eller man ekstraherer med T^O, hvis alkoholen ikke er blandbar med HgO).The reaction mixture is cooled and a corresponding amount of t 2 O is added (or extracted with T 2 O if the alcohol is not miscible with HgO).
Man fjerner den overskydende svovlsyre ved at indstille 25 pH til 3 ved tilsætning af en basisk ionbytterharpiks på 0H"-form (AMBERLITE® IRA 401 eller AMBERLITE® IRA 93).The excess sulfuric acid is removed by adjusting 25 pH to 3 by the addition of a basic ion exchange resin of 0H "form (AMBERLITE® IRA 401 or AMBERLITE® IRA 93).
Ionbytterharpiksen filtreres fra og sendes til regenerering .The ion exchange resin is filtered off and sent for regeneration.
6 1*9967 Når der er tale om alkoholer, som kan blandes med vand, afdampes alkoholen under vakuum.6 1 * 9967 In the case of alcohols which can be mixed with water, the alcohol is evaporated under vacuum.
Hvis mængden af resterende SAM i opløsningen, som er opnået på denne måde, overskrider 15K, koges opløsningen i 5 20 minutter med henblik på at destruere den resterende SAM.If the amount of SAM remaining in the solution thus obtained exceeds 15K, the solution is boiled for 5 20 minutes to destroy the remaining SAM.
Man indstiller pH-værdien til 6,5 under omrøring, hvorefter man leder opløsningen igennem en kolonne indeholdende en svagt sur ionbytterharpiks på H+-form (AMBERLITE^ 10 IRC 50 eller CG 50), som på forhånd er vasket med H2O, idet man overholder de følgende parametre for driften af kolonnen: forholdet imellem diameteren og højden af harpiks-fyldningen skal være 1:10; 15 der påfyldes 20 g SAM-ester pr. liter harpiks, og strømningen skal være 1 kolonnevolumen pr. time.The pH is adjusted to 6.5 with stirring, then the solution is passed through a column containing a slightly acidic H + exchange resin (AMBERLITE ^ 10 IRC 50 or CG 50) which has been pre-washed with H the following parameters for the operation of the column: the ratio between the diameter and the height of the resin filling must be 1:10; 15 grams of 20 g of SAM ester are added per day. liters of resin and the flow should be 1 column volume per liter. hour.
Derefter vaskes kolonnen med 1 kolonnevolumen H2O og 0,1 N eddikesyre, indtil pH i eluatet er 3. Derpå vaskes kolonnen med yderligere 1 volumen vand.Then the column is washed with 1 column volume of H2O and 0.1 N acetic acid until the pH of the eluate is 3. Then the column is washed with an additional 1 volume of water.
23 SAM-esteren elueres med 0,1 N svovlsyre (eller med en an den stærk syre, hvis man ønsker et andet salt).23 The SAM ester is eluted with 0.1 N sulfuric acid (or with the strong acid if another salt is desired).
Den således opnåede opløsning koncentreres under vakuum til 50 g/1.The solution thus obtained is concentrated in vacuo to 50 g / l.
Man filtrerer den koncentrerede opløsning med aktiveret 25 trækul (1/10 af SAM-esteren), og man indstiller syresam mensætningen til den krævede værdi (3-5 ækvivalenter, fortrinsvis 4 ækvivalenter) ved tilsætning af koncentreret H2S0^ (eller en anden stærk syre), hvorpå man lyophi-liserer opløsningen.The concentrated solution is filtered with activated charcoal (1/10 of the SAM ester) and the acid composition is adjusted to the required value (3-5 equivalents, preferably 4 equivalents) by the addition of concentrated H2SO4 (or another strong acid ) on which to lyophilize the solution.
149957 7149957 7
Opfindelsen illustreres nærmere ved de følgende eksempler.The invention is further illustrated by the following examples.
EKSEMPEL 1EXAMPLE 1
En mængde SAM-sulfat, der svarer til 1 kg SAM-ioner, opløses i 20 liter methanol, der indeholder 2 volumen-% kon-5 centreret svovlsyre. Opløsningen opvarmes under tilbagesvaling i 16 timer. Den afkøles og fortyndes med 20 liter destilleret vand.An amount of SAM sulfate corresponding to 1 kg of SAM ions is dissolved in 20 liters of methanol containing 2% by volume of concentrated sulfuric acid. The solution is heated at reflux for 16 hours. It is cooled and diluted with 20 liters of distilled water.
Derefter behandles opløsningen med AMBERLITE^RA 93 ion-bytterharpiks (på forhånd aktiveret med 2 N natriumhy-10 droxid og vasket indtil neutral reaktion) indtil pH-vær- dien er 3. Der anvendes omkring 15 liter ionbytterharpiks.Then, the solution is treated with AMBERLITE ^ RA 93 ion exchange resin (pre-activated with 2N sodium hydroxide and washed until neutral reaction) until the pH is 3. About 15 liters of ion exchange resin are used.
Blandingen filtreres og vaskes med destilleret vand. Derefter afdampes methanolen under vakuum. Opløsningen koges i 20 minutter med henblik på at fjerne de sidste spor af 15 ikke-omsat SAM, hvorefter den afkøles.The mixture is filtered and washed with distilled water. Then the methanol is evaporated under vacuum. The solution is boiled for 20 minutes to remove the last traces of 15 unreacted SAM and then cooled.
Der fremstilles en kolonne indeholdende AMBERLITE®IRV 50 ionbytterharpiks på H+-form indeholdende 40 liter harpiks aktiveret med 100 liter 0,5 N svovlsyre og vasket indtil neutral reaktion. Den tidligere opnåede opløsning neutra-20 liseres til pH 6,5 ved hjælp af 2 N natriumhydroxid og ledes igennem kolonnen med en hastighed på 40 liter/time.A column containing AMBERLITE® IRV 50 H + ion exchange resin containing 40 liters of resin activated with 100 liters of 0.5 N sulfuric acid is prepared and washed until neutral reaction. The previously obtained solution is neutralized to pH 6.5 using 2N sodium hydroxide and passed through the column at a rate of 40 liters / hour.
Kolonnen vaskes med 40 liter vand.The column is washed with 40 liters of water.
Der ledes en 0,1 N eddikesyreopløsning igennem kolonnen, 149957 8 indtil eluatet udviser en pH-værdi på 3 (omkring 200 liter) efterfulgt af 40 liter destilleret vand.A 0.1 N acetic acid solution is passed through the column until the eluate exhibits a pH of 3 (about 200 liters) followed by 40 liters of distilled water.
Der elueres med 60 liter 0,1 N svovlsyre. Eluatet koncentreres under vakuum (35 °C, 30 mm Hg) til et volumen på 5 omkring 10 liter, hvorefter der tilsættes 50 g aktiveret trækul. Blandingen filtreres, og opløsningen titreres.Elute with 60 liters of 0.1 N sulfuric acid. The eluate is concentrated under vacuum (35 ° C, 30 mm Hg) to a volume of about 10 liters, after which 50 g of activated charcoal is added. The mixture is filtered and the solution is titrated.
Der tilsættes en mængde koncentreret svovlsyre, som er tilstrækkelig til at opnå et molært forhold imellem SAM-methylester og svovlsyre på 1:2, hvorefter opløsningen 10 lyophiliseres.An amount of concentrated sulfuric acid sufficient to obtain a molar ratio of SAM methyl ester to 1: 2 sulfuric acid is added and the solution 10 is lyophilized.
Der opnås 820 g produkt, hvis sammensætning er følgende: - SAH-methylester 66,8¾ - H2S04 31,7¾ - H20 1,5¾ 15 dette svarer til et udbytte på 54,7¾ med hensyn til SAM- ioner.820 g of product are obtained, the composition of which is as follows: - SAH methyl ester 66.8¾ - H₂SO4 31.7¾ - H₂O 1.5¾ 15 this corresponds to a yield of 54.7¾ for SAM ions.
Når produktet analyseres ved højtryksvæskechromatografi (kolonne: PARTISlfrlO SCX, eluent: 0,1 M ammoniumformiat, pH 4, 20¾ methanol, strømningshastighed: 1 ml/min), udvi-20 ser det et enkelt udsving med en retentionstid på 580 sekunder.When the product is analyzed by high pressure liquid chromatography (column: PARTISlfrlO SCX, eluent: 0.1 M ammonium formate, pH 4, 20¾ methanol, flow rate: 1 ml / min), it exhibits a single fluctuation with a retention time of 580 seconds.
Produktet blev identificeret ved sine UV- og NMR-spektre med følgende resultater: UV-spektrum: 25 Ved pH 4: absorptionsmaksimum ved 258 nm med ζ. = 14040, ved pH 1: absorptionsmaksimum ved 256 nm med £, = 13500.The product was identified by its UV and NMR spectra with the following results: UV spectrum: 25 At pH 4: absorption maximum at 258 nm with ζ. = 14040, at pH 1: absorption maximum at 256 nm with £, = 13500.
149957 9 NMR-spektrum:NMR spectrum:
Ved 3 p.p.m: singlet fra !a-CH j-gruppen, ved 3,7 p.p.m.j singlet fra R-C-O-CH^-gruppen.At 3 ppm: singlet from the a-CH 2 group, at 3.7 ppm singlet from the R-C-O-CH 2 group.
HH
Hvis den støkiometriske sammensætning inden lyophiliserin-5 gen indstilles til et forhold imellem SAM-methylester og svovlsyre på 1:1,5 eller 1:2,5, og opløsningen derefter lyophiliseres, opnås de følgende respektive salte: - SAM-methylester . 1,5 H2S04 . 0,5H20 - SAM-methylester . 2,5 H2S04 . 0,5H20 10 Hvis IRC 50-kolonnen elueres med saltsyre i stedet for med svovlsyre, opnås følgende salte: - SAM-methylester . 3 HC1 . 0,5H20 - SAM-methylester . 4 HC1 . 0,5H20 - SAM-methylester . 5 HC1 . 0,5H20.If the stoichiometric composition before the lyophiliser 5 is adjusted to a ratio of SAM methyl ester to sulfuric acid of 1: 1.5 or 1: 2.5 and the solution is then lyophilized, the following respective salts are obtained: - SAM methyl ester. 1.5 H 2 SO 4. 0.5 H 2 O - SAM methyl ester. 2.5 H2 SO4. 0.5H 2 O 10 If the IRC 50 column is eluted with hydrochloric acid instead of sulfuric acid, the following salts are obtained: - SAM methyl ester. 3 HCl. 0.5 H 2 O - SAM methyl ester. 4 HCl. 0.5 H 2 O - SAM methyl ester. HCl. 0,5H20.
15 Tilsvarende kan man ved at anvende methansulfonsyre opnå de tilsvarende methansulfonater.Similarly, by using methanesulfonic acid, the corresponding methanesulfonates can be obtained.
De analytiske data for disse salte er anført i den følgende tabel: 149957 10 ε ο ,—I Ι-^ΟΟΉΙΛΟΟΙΛΟΟΜ}· Ό II CM ι—I νΟ ΙΛ Ον Ρ- ΙΛ s? CMCMCMCMCMCMi-li-H ΜThe analytical data for these salts are given in the following table: 149957 10 ε ο, —I Ι- ^ ΟΟΉΙΛΟΟΙΛΟΟΜ} · Ό II CM ι — I νΟ ΙΛ Ον Ρ- ΙΛ s? CMCMCMCMCMCMi-li-H Μ
ι—I Xι — I X
UJ α.UJ α.
jJMiHCvJrHiAONONVO m øOvor^OOCMCJvCO ΙΛ X) „„•.•»•'Λ·'·'·' r* - < ιΛ 'Λ 'Λ ιΛ ΙΛ Λ- O' 1-1jJMiHCvJrHiAONONVO m øOvor ^ OOCMCJvCO ΙΛ X) „„ •. • »• 'Λ ·' · '·' r * - <ιΛ 'Λ' Λ ιΛ ΙΛ Λ- O '1-1
□ ιΗ -Η >-1 Ή 1-1 CM□ ιΗ -Η> -1 Ή 1-1 CM
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• □ ·ο ο · · .· · x *x *χ Μ CM 04 CM Μ CM t4 ¢4 (4 ί-ιΙΛί4ΐΛ{4ΐΛ mx ojx ωχ ωο ωο ωο ω - ω - ω ·- 4-1 ΙΛ 44 ΙΛ 44 ΙΛ 44CM4JCM44CM440 4->0 440 ω - ω - ω - ωχ ωχ ωχ ω· ω· ω· ωο ωο ωο ο uj ν ιλ ο ιλ ωχ ωχ ωχ ι-4· ιΗ· ,—I · ι—I — ι—I — ι—I — ι—I ΓΛ ι—11 ΙΛ ι—I ΙΛ _j 0Λ4τ>,<*>,4ί>>ο >· ο >· α >· ο >· ο >- ο lj 44 χ ο χ ο χ ο χ · χ χ · χιη χ m xtn 0Q ιΗ 43 in 4Jtn 4Jtn 4Ji-l 4J1-I 44 ·Η 44 ΙΛ 44 ΙΛ 44 ΓΛ a: co (DCMCDCMiDCMajcj ωο ωο ωχ ωχ ωχ ι- tn ε χ XX XX XX XX XX χο χο χο 149957 11 EKSEMPEL 2• □ · ο ο · ·. · · X * x * χ CM 04 CM Μ CM t4 ¢ 4 (4 ί-ιΙΛί4ΐΛ {4ΐΛ mx ojx ωο ωο ωο ω - ω - ω · - 4-1 ΙΛ 44 ΙΛ 44 ΙΛ 44CM4JCM44CM440 4-> 0 440 ω - ω - ω - ωχ ωχ ωχ ω · ω · ω · ωο ωο ωο ο uj ν ιλ ο ιλ ωχ ωχ ωχ ι-4 · ιΗ ·, —I · ι — I —I - ι — I - ι — I ΓΛ ι — 11 ΙΛ ι — I ΙΛ _j 0Λ4τ>, <*>, 4ί >> ο> · ο> · α> · ο> · ο> - ο lj 44 χ ο χ ο ο χ · χ χ · χιη χ m xtn 0Q ιΗ 43 in 4Jtn 4Jtn 4Ji-l 4J1-I 44 · Η 44 ΙΛ 44 ΙΛ 44 ΓΛ a: co (DCMCDCMiDCMajcj ωο ωο ωχ ωχ ωχε EXAMPLE 2 XX XX XX XX 11ο χο χο 149957 11
Man følger den samme procedure som beskrevet i eksempel 1, idet der anvendes absolut ethanol indeholdende 2¾ svovlsyre .Follow the same procedure as described in Example 1, using absolute ethanol containing 2¾ sulfuric acid.
5 Der opnås en SAM-ethylester med formlen: SAM-ethylester. 2H2S04· 0,5HZ0 UV-spektrum: ved pH 4: absorptionsmaksimum ved 258 nm med £. = 14040 10 ved pH 1: absorptionsmaksimum ved 256 nm med £. = 13500 NMR-spektrum: ved 1,25 p.p.m.: triplet fra R-CH^-gruppen ved 3 p.p.m.: singlet fra $-CH^-gruppen ved 4,2 p.p.m.: kvartet fra R-jj-0-CH2-R-gruppen Når produktet analyseres ved højtryksvæskechromatografi 15 under de i eksempel 1 beskrevne betingelser, giver det et enkelt udslag med en retentionstid på 600 sekunder.A SAM ethyl ester of the formula: SAM ethyl ester is obtained. 2 H 2 SO 4 · 0.5 H 2 O UV spectrum: at pH 4: absorption maximum at 258 nm with £. = 14040 10 at pH 1: absorption maximum at 256 nm with £. = 13500 NMR spectrum: at 1.25 ppm: tripled from the R-CH 2 group at 3 ppm: singlet from the $ -CH 2 group at 4.2 ppm: quartered from R-Y-O-CH 2 -R- the group When the product is analyzed by high pressure liquid chromatography under the conditions described in Example 1, it gives a single result with a retention time of 600 seconds.
Ligesom i eksempel 1 er det muligt at opnå en hel række salte, nærmere bestemt: - SAM-ethylester. 1,5H2S04· 0,5H20 20 - SAM-ethylester. 2,5H2S04· 0,5H20 - SAM-ethylester. 3HC1. 0,5H20 - SAM-ethylester. 4HC1. 0,5H20 - SAM-ethylester. 5HC1. 0,5H20 - SAM-ethylester. 3CH^S0^H. 0,5M20 25 - SAM-ethylester. 4CH^S0^H. 0,5H20 - SAM-ethylester. 5CH^S0-jH. 0,5H20.As in Example 1, it is possible to obtain a whole series of salts, in particular: - SAM ethyl ester. 1.5 H 2 SO 4 · 0.5 H 2 O 20 - SAM ethyl ester. 2.5 H 2 SO 4 · 0.5 H 2 O - SAM ethyl ester. 3HC1. 0.5 H 2 O - SAM ethyl ester. 4HC1. 0.5 H 2 O - SAM ethyl ester. 5HC1. 0.5 H 2 O - SAM ethyl ester. S0 3 CH ^ H ^. 0.5M20 25 - SAM ethyl ester. S0 4 CH ^ H ^. 0.5 H 2 O - SAM ethyl ester. 5CH ^ S0 JH. 0,5H20.
149957 12149957 12
Alle disse salte har UV- og NMR-spektre, der er identiske med spektrene for det ovennævnte salt.All of these salts have UV and NMR spectra that are identical to the spectra of the above salt.
EKSEMPEL 3EXAMPLE 3
Man følger den i eksempel 1 beskrevne procedure, idet der 5 anvendes n-butanol indeholdende 2% svovlsyre.The procedure described in Example 1 is followed, using n-butanol containing 2% sulfuric acid.
Der opnås omgående en suspension, som omdannes til en klar opløsning ved opvarmning under tilbagesvaling.A suspension is obtained immediately which is converted to a clear solution by reflux heating.
Herved opnås en SAM-n-butylester med formlen: SAM-n-butylester. 2H2S0^. 0,5H20 10 UV-spektrum: ved pH 4: absorptionsmaksimum ved 258 nm med £, = 14040 ved pH 1: absorptionsmaksimum ved 256 nm med 6. = 13500.There is thus obtained a SAM-n-butyl ester of the formula: SAM-n-butyl ester. 2H2S0 ^. 0.5 H 2 O 10 UV spectrum: at pH 4: absorption maximum at 258 nm with £ = 14040 at pH 1: absorption maximum at 256 nm with 6. = 13500.
NMR-spektrum: ved 0,9 p.p.m.: triplet karakteristisk for R-CH^-gruppen 15 ved 3 p.p.m.: singlet fra §-CH^-gruppen ved 4,1 p.p.m.: kvartet karakteristisk for R-C-O-CH2-R- y gruppen.NMR spectrum: at 0.9 p.p.m .: triplet characteristic of the R-CH 2 group 15 at 3 p.m .: singlet of the §-CH 2 group at 4.1 p.m .: quartet characteristic of the R-C-O-CH 2 -R-γ group.
Når produktet analyseres ved højtryksvæskechromatografi under de i eksempel 1 beskrevne betingelser, giver det 20 et enkelt udslag med en retentionstid på 650 sekunder.When the product is analyzed by high pressure liquid chromatography under the conditions described in Example 1, it gives a single result with a retention time of 650 seconds.
Hele rækken af salte fra eksemplerne 1 og 2 blev opnået under de samme betingelser som beskrevet ovenfor.The entire series of salts of Examples 1 and 2 were obtained under the same conditions as described above.
Ved at anvende n-pentanol og n-hexanol i stedet for butanol opnåedes SAM-n-pentyl- og n-hexylesterne.Using n-pentanol and n-hexanol in place of butanol, the SAM-n-pentyl and n-hexyl esters were obtained.
U9957 13U9957 13
Den efterfølgende tabel angiver de analytiske data for SAM-esterne fra eksempel 2 og 3.The following table gives the analytical data for the SAM esters of Examples 2 and 3.
149957 14 ε o μ cm r— ια co vf149957 14 ε o μ cm r— ια co vf
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Biologisk rapportBiological report
Alle forbandelserne ifølge opfindelsen er afprøvet i et bredspektret farmakologisk undersøgelsesprogram, og i alle tilfælde har disse forbindelser udvist særdeles interessante aktivitets- og toxicitets-karakte-5 ristika.All the compounds of the invention have been tested in a broad spectrum pharmacological study program, and in all cases these compounds have shown extremely interesting activity and toxicity characteristics.
Det viste sig, at aktiviteten af de omhandlede forbindelse i det væsentlige afhænger af disse forbindelsers evne til at frigøre SAM+-ioner i organismen og af disse ioners evne til at virke som donorer for methylgrupper som det 10 naturlige substrat for et stort antal transmethylase-en- zymer, der katalyserer fundamentale reaktioner i lipid-, protid- og glucocid-metabolismen.It was found that the activity of the subject compound depends essentially on the ability of these compounds to release SAM + ions in the organism and on the ability of these ions to act as donors for methyl groups as the natural substrate for a large number of transmethylase. - enzymes that catalyze fundamental reactions in lipid, protide and glucocide metabolism.
De omhandlede forbindelsers betydning kan således i det væsentlige udledes af det faktum, at de gør S-adenosyl-15 methionin absolut stabil, hvorved det bliver muligt at udnytte denne forbindelses transmethylerende virkning i den menneskelige organisme 100% uden risiko for dannelse af toxiske nedbrydningsprodukter, som udviser en skadelig virkning på de biologiske processer, der aktiveres af SAM+-20 ionerne.Thus, the significance of the compounds of the invention can be deduced essentially from the fact that they render S-adenosyl-methionine absolutely stable, thereby enabling the transmethylating effect of this compound to be utilized 100% in the human organism without the risk of formation of toxic degradation products. which exhibit a deleterious effect on the biological processes activated by the SAM + -20 ions.
Forbindelsernes betydning skyldes også deres evne til at gøre SAM i stand til at passere igennem cellebarierer og derved gøre denne forbindelse særdeles biotilgængelig.The significance of the compounds is also due to their ability to enable SAM to pass through cell barriers, thereby making this compound highly bioavailable.
Toxicitet 25 Man har bestemt den akutte toxicitet hos mus, og i alle tilfælde opnåedes følgende værdier: LD^q ved oral administration ^ 3 g/kg LD^0 ved intravenøs administration > 1 g/kg.Toxicity Acute toxicity has been determined in mice, and in all cases the following values were obtained: LD 2 q by oral administration 3 g / kg LD 2 0 by intravenous administration> 1 g / kg.
Undersøgelser af tolerancen og den kroniske toxicitet 30 blev gennemført på rotter af stammerne Wistar og Sprague- 149957 16Tolerance and chronic toxicity studies 30 were conducted on rats of the Wistar and Sprague strains.
Dowley, idet man indgav forbindelserne i doser på 20 mg/kg pr. dag i 12 måneder. Ued behandlingens afslutning udviste de forskellige organer og systemer ingen patologiske ændringer.Dowley, administering the compounds at doses of 20 mg / kg per day. day for 12 months. At the end of treatment, the various organs and systems showed no pathological changes.
5 Man har udført teratogenese-forsøg på kaniner. Ued indgivelse af saltene i doser, som var 10 gange større end den maksimale terapeutiske dosis, konstaterede man ikke nogen teratogen virkning eller misdannende virkning på fostrene eller på de terminale fostre.5 Teratogenesis experiments on rabbits have been performed. Without administration of the salts at doses 10 times greater than the maximum therapeutic dose, no teratogenic or malformative effect was observed on the fetuses or on the terminal fetuses.
10 Intravenøse indgivelser af doser på op til 200 mg/kg bevirkede ikke nogen pyrogene manifestationer hos kaniner.Intravenous administration of doses up to 200 mg / kg did not cause any pyrogenic manifestations in rabbits.
En venøs administration på 40 mg/kg til kaniner og rotter bevirker ingen ændringer i trykket i halspulsåren eller i hjerte- og respirationsfrekvensen, og der iagttages heller 15 ingen ændringer i elektrocardiogrammets form.A venous administration of 40 mg / kg to rabbits and rats causes no changes in the pressure in the carotid artery or in the heart and respiratory rate, and no changes in the shape of the electrocardiogram are observed.
Den lokale tolerance ved intramuskulære injektioner, også efter gentagne indgivelser i 30 - 60 dage, og ved intravenøse injektioner i den marginale vene i det ydre øre hos kaniner har vist sig at være fremragende.The local tolerance for intramuscular injections, also after repeated administration for 30 - 60 days, and for intravenous injections into the marginal vein of the outer ear of rabbits has been found to be excellent.
20 Farmakologi20 Pharmacology
En lang række forsøg udført på rotter har vist, at de hidtil ukendte forbindelser ifølge opfindelsen udviser en meget betragtelig beskyttende og helbredende virkning på steatosis hepatis induceret ved hjælp af en hyperlipid-25 hyperprotein-diæt i overensstemmelse med metoden beskrevet af Handler, og på steatosis induceret ved akut alkoholfor giftning og ved hjælp af andre toxiske midler, også når der indgives doser på 10 mg/kg SAM+.A variety of experiments on rats have shown that the novel compounds of the invention exhibit a very significant protective and curative effect on steatosis hepatitis induced by a hyperlipid hyperprotein diet in accordance with the method described by Handler and on steatosis. induced by acute alcohol poisoning and by other toxic agents, even when doses of 10 mg / kg SAM + are administered.
Med hensyn til hyperlipidæmi hos rotter, eksempelvis in-30 duceret med Triton S, har de omhandlede produkter udvist 149957 17 en meget iøjnefaldende hypolipedæmisk virkning, som, i relation til den anvendte dosis, dvs. 10 mg/kg (igen udtrykt i SAM+), var meget mere intens end i det tilfælde, hvor der anvendtes andre medikamenter med hypolipidæmisk 5 virkning.With regard to hyperlipidemia in rats, for example induced with Triton S, the products in question exhibited a very conspicuous hypolipidemic effect which, in relation to the dose used, ie. 10 mg / kg (again expressed in SAM +), was much more intense than in the case of other hypolipidemic 5 drugs.
Hos kyllinger, som er gjort atherosclerotiske ved indgivelse af diæter beriget med cholesterol og fructose, kan en parenteral indgivelse af forbindelserne ifølge opfindelsen i doser på 10 mg/kg reducere forekomsten af chole-10 sterolemi og på favorabel måde modificere de læsioner, som iagttages hos kontroldyr med hensyn til den torakale og abdominale aorta og de små kar i hjernens basis.In chickens rendered atherosclerotic by administration of diets enriched with cholesterol and fructose, a parenteral administration of the compounds of the invention at doses of 10 mg / kg may reduce the incidence of cholesterol sterilization and favorably modify the lesions observed in control animals for the thoracic and abdominal aorta and the small vessels in the brain base.
Med hensyn til phosphorlipid-metabolismen har det eksperimentelt vist sig, at der sker en forøgelse af mængde af 15 phosphatidylcholin i hjernevævet hos rotter med ikke-kom- penseret steatosis. En tydelig forøgelse i indholdet af phosphatidylcholin kunne også bestemmes på bekostning af de hæmatiske oi-lipoproteiner i eksperimentelle ændringer fremkaldt af β/α-lipoprotein-forholdene.With regard to phosphorus lipid metabolism, it has been experimentally shown to increase the amount of phosphatidylcholine in the brain tissue of rats with uncompensated steatosis. A marked increase in the content of phosphatidylcholine could also be determined at the expense of the haematic oi-lipoproteins in experimental changes induced by the β / α-lipoprotein ratios.
20 Alle disse forsøg har klart vist, at de omhandlede forbindelser har en helbredende virkning ved ændringer af lipid-metabolismen. En yderligere række af forsøg udført på rotter har vist, at en indgivelse på 1 mg/kg bevirker en akkumulering af de glycogene reserver på lever- og muskel-25 niveau, hvilket er eftervist ved såvel histokemiske metoder som ved kvantitative bestemmelser. I eksperimentelt fremkaldt diabetes induceret med alloxan har den mængde insulin, som er påkrævet for at bringe glykæmi-værdier-ne tilbage til normalt niveau, kunnet reduceres b'etrag-30 teligt ved indgivelser svarende til 0,5 mg/kg SAM+.All of these experiments have clearly shown that the compounds of this invention have a curative effect on changes in lipid metabolism. A further series of experiments in rats have shown that administration of 1 mg / kg causes an accumulation of the glycogenic reserves at the liver and muscle levels, as evidenced by both histochemical and quantitative assays. In experimentally induced diabetes induced with alloxane, the amount of insulin required to bring the glycemia levels back to normal levels has been significantly reduced by administration of 0.5 mg / kg SAM +.
Denne række af forsøg har udvist en klart positiv virkning af forbindelserne fremstillet ifølge opfindelsen på giycosidmetabolismen.This series of experiments has shown a clearly positive effect of the compounds of the invention on the glycoside metabolism.
149957 18149957 18
Endelig har man behandlet rotter med eksperimentelt induceret hypodisproteinæmi med SAM-estere i mængder på 10 mg/kg. Det viste sig, at disse produkter bevirker, at-de totale proteinæmi-værdier vender tilbage til normale ni-5 veauer, idet der sker en væsentlig forøgelse af albuminniveauet, og således udviser de omhandlede forbindelser en bemærkelsesværdig protein-anabolisk virkning.Finally, rats with experimentally induced hypodysproteinemia have been treated with SAM esters in amounts of 10 mg / kg. It was found that these products cause the total proteinemia values to return to normal levels, with a substantial increase in the albumin level, and thus the compounds of the invention exhibit a remarkable protein anabolic effect.
Disse og andre forsøg har eftervist den kurative aktivitet af de omhandlede forbindelser overfor forstyrrelser i pro-10 tid-metabolismen.These and other experiments have demonstrated the curative activity of the compounds of the present invention against disorders of pro-10 metabolism.
Sammenfattende kan det på basis af de ovenfor beskrevne farmakologiske forsøg og på basis af mange andre forsøg, som har gjort det muligt at klarlægge virkningen af de omhandlede forbindelser på alle niveauer i den menneske-15 lige organisme, siges, at de omhandlede forbindelsers virkning er klinisk fastslået inden for hepatologien, når der er tale om akutte og kroniske leverforgiftninger, inden for neurologien, når der er tale om den antidepressi-ve virkning, og inden for osteologien, når.der er tale om 20 rhenmatoid arthritis.In summary, on the basis of the pharmacological tests described above and on the basis of many other tests which have made it possible to clarify the effect of the compounds in question at all levels of the human organism, it can be said that the effect of the compounds in question is clinically established in the field of hepatology in the case of acute and chronic liver poisonings, in the neurology in the case of the antidepressant effect, and in the osteology in the case of 20 rhenmatoid arthritis.
Forbindelsernes virkning inden for et antal andre områder af den humane terapi er for øjeblikket under udforskning.The effect of the compounds in a number of other areas of human therapy is currently under investigation.
Forbindelserne har også ganske uventet udvist en betragtelig antiinflammatorisk og analgetisk virkning.The compounds have also, quite unexpectedly, shown a considerable anti-inflammatory and analgesic effect.
25 Forbindelserne fremstillet ifølge opfindelsen kan indgives o- ralt, eller de kan indgives ved intramuskulær eller intravenøs injektion. Da forbindelserne imidlertid udmærker sig ved en større intestinal absorption end SAM, er de specielt nyttige til fremstilling af farmaceutiske formuleringer 30 til oral anvendelse.The compounds of the invention may be administered orally or may be administered by intramuscular or intravenous injection. However, since the compounds are characterized by greater intestinal absorption than SAM, they are particularly useful in the preparation of pharmaceutical formulations 30 for oral use.
149957 19149957 19
Blandt de andre mulige indgivelsesformer kan anføres stikpiller, væsker til okular installation, aerosoler og salver til topisk påføring.Other possible forms of administration may include suppositories, ocular installation fluids, aerosols and ointments for topical application.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT23940/81A IT1139974B (en) | 1981-09-11 | 1981-09-11 | DERIVATIVES OF S-ADENOSYLMETHIONINE, PROCESS FOR PREPARATION AND THERAPEUTIC COMPOSITIONS THAT CONTAIN THEM AS AN ACTIVE INGREDIENT |
| IT2394081 | 1981-09-11 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK405382A DK405382A (en) | 1983-03-12 |
| DK149957B true DK149957B (en) | 1986-11-03 |
| DK149957C DK149957C (en) | 1987-06-15 |
Family
ID=11211012
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK405382A DK149957C (en) | 1981-09-11 | 1982-09-10 | METHOD OF ANALOGUE FOR THE PREPARATION OF S-ADENOSYL-METHIONINE ESTERS |
| DK349085A DK155332C (en) | 1981-09-11 | 1985-08-01 | METHOD OF ANALOGY FOR THE PREPARATION OF S-ADENOSYLMETHIONIN DERIVATIVES |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK349085A DK155332C (en) | 1981-09-11 | 1985-08-01 | METHOD OF ANALOGY FOR THE PREPARATION OF S-ADENOSYLMETHIONIN DERIVATIVES |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US4558122A (en) |
| EP (1) | EP0074555B1 (en) |
| JP (1) | JPS5857397A (en) |
| AT (1) | ATE14884T1 (en) |
| AU (1) | AU564577B2 (en) |
| CA (1) | CA1213886A (en) |
| CS (1) | CS241123B2 (en) |
| DE (1) | DE3265425D1 (en) |
| DK (2) | DK149957C (en) |
| ES (1) | ES515613A0 (en) |
| FI (1) | FI74290C (en) |
| GR (1) | GR76720B (en) |
| HU (1) | HU186117B (en) |
| IL (1) | IL66713A (en) |
| IT (1) | IT1139974B (en) |
| MX (1) | MX5670A (en) |
| NO (1) | NO153397C (en) |
| NZ (1) | NZ201824A (en) |
| PL (1) | PL141706B1 (en) |
| PT (1) | PT75516B (en) |
| RO (1) | RO85286B (en) |
| RU (1) | RU2041235C1 (en) |
| SU (1) | SU1340592A3 (en) |
| YU (1) | YU43092B (en) |
| ZA (1) | ZA826408B (en) |
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| IT1169773B (en) * | 1983-08-24 | 1987-06-03 | Bioresearch Spa | PROCESS FOR THE PRODUCTION OF STABLE SALTS OF SULPHO-ADENOSYL-L-METHIONINE |
| CA1291092C (en) * | 1988-03-11 | 1991-10-22 | Donald A. Poole | Easy opening gable top carton |
| IT1229514B (en) * | 1989-01-30 | 1991-09-03 | Farmhispania S A A Montme | SYNTHETIC AMPHIPHILIC GLYCOCONUGATES FOR NEUROLOGICAL USE. |
| JPH02290896A (en) * | 1989-04-28 | 1990-11-30 | Fuji Kagaku Kogyo Kk | Novel s-adenosylmethionine derivative |
| US5180714A (en) * | 1990-10-31 | 1993-01-19 | Health Research, Inc. | Adenosine compounds for the treatment of diseases caused by parasitic protozoa |
| US8642581B1 (en) | 2000-02-11 | 2014-02-04 | Brian D. Halevie-Goldman | Compositions and methods for the production of S-adenosylmethionine within the body |
| US6649753B2 (en) * | 2001-06-07 | 2003-11-18 | Orchid Chemicals & Pharmaceuticals Ltd. | Stable salts of S-adenosyl-L-methionine (SAMe) and the process for their preparation |
| US20040116351A1 (en) * | 2002-12-06 | 2004-06-17 | Fast Balance, Inc. | Method for enhancing the natural reward system for exercise |
| US20050272687A1 (en) * | 2004-06-08 | 2005-12-08 | Hebert Rolland F | Stable S-adenosyl-l-methionine |
| US20090012036A1 (en) * | 2005-05-24 | 2009-01-08 | Hebert Rolland F | Stable S-adenosyl-L-methionine |
| ITMI20060629A1 (en) * | 2006-03-31 | 2007-10-01 | Daniele Giovannone | ORAL SOLID COMPOSITIONS BASED ON S-ADENOSYLMETIONINE AND PROCESS FOR THEIR ACHIEVEMENT |
| JP2008013509A (en) * | 2006-07-07 | 2008-01-24 | Fujifilm Corp | Method for preserving s-adenosylmethionine |
| ITMI20071374A1 (en) * | 2007-07-10 | 2009-01-11 | Gnosis Spa | STABLE STABLE OF S-ADENOSYLMETHIONINE AND PROCESS FOR THEIR ACHIEVEMENT. |
| US20100004191A1 (en) * | 2008-07-01 | 2010-01-07 | Rolland F Hebert | Compositions of S-adenosyl-L-methionine. |
| WO2012016704A1 (en) | 2010-08-05 | 2012-02-09 | Cellzome Ag | Methods for the identification of methyltransferase interacting molecules and for the purification of methyltransferase proteins |
| WO2014113609A1 (en) | 2013-01-16 | 2014-07-24 | Hebert Sam-E Llc | Stable indole-3-propionate salts of s-adenosyl-l-methionine |
| WO2015028927A1 (en) * | 2013-08-25 | 2015-03-05 | Mahesh Kandula | Compositions and methods for the treatment of metabolic diseases |
| EP3153414B1 (en) | 2015-10-05 | 2018-04-11 | Tetra Laval Holdings & Finance S.A. | An applying unit for applying a lid onto a container |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2969353A (en) * | 1957-02-06 | 1961-01-24 | Merck & Co Inc | Process for the preparation of "active methionine" and products obtained thereby |
| DE1803978C2 (en) * | 1968-10-18 | 1985-05-02 | Boehringer Mannheim Gmbh, 6800 Mannheim | Process for the production of S-adenosyl-l-methionine and S-adenosyl-l-ethionine |
| IE37913B1 (en) * | 1972-08-02 | 1977-11-09 | Bioresearch Sas | Salt of s-adenosyl-l-methionine |
| IE39517B1 (en) * | 1973-06-27 | 1978-10-25 | Bioresearch Sas | Double salts of s-adenosyl-l-methhionine |
| US4028183A (en) * | 1973-06-27 | 1977-06-07 | Bioresearch Limited | Process of preparing double salts of S-adenosyl-L-methionine |
| JPS5320998B2 (en) * | 1974-06-13 | 1978-06-29 | ||
| FR2275220A1 (en) * | 1974-06-21 | 1976-01-16 | Merieux Inst | Organic salts of S-adenosyl-L-methionine - prepd. by fixing the methionine on resin and eluting with the appropriate organic acid |
| AR221676A1 (en) * | 1974-07-12 | 1981-03-13 | Bioresearch Sas | PROCEDURE FOR THE PREPARATION OF SULPHONIC AND / OR SULFURIC STABLE SALTS OF S-ADENOSIL-L-METIONINE, PARTICULARLY USEFUL AS SPECIFIC METHYL DONORS FOR THE CH3, ELAMIBLI-TRANSFERRING BIOCHEMICAL AND LATIN-GLOBAL ELEMENTS PROTILICO AND GLUCIDICO |
| GB2001976B (en) * | 1977-08-03 | 1982-03-10 | Yamasa Shoyu Kk | S-adenosyl-l-methionine compositions and production thereof |
| GB2064523B (en) * | 1979-12-04 | 1983-06-29 | Kanegafuchi Chemical Ind | Stable composition of s-adenosyl-l-methionine |
| JPS5699499A (en) * | 1980-01-10 | 1981-08-10 | Kanegafuchi Chem Ind Co Ltd | Composition containing s-adenosyl-l-methionine, and its preparation |
| JPS56145299A (en) * | 1980-04-11 | 1981-11-11 | Kanegafuchi Chem Ind Co Ltd | Purification of s-adenosyl-l-methionine |
| JPS57156500A (en) * | 1981-03-23 | 1982-09-27 | Kanegafuchi Chem Ind Co Ltd | Composition containing s-adenosyl-l-methionine and its preparation |
-
1981
- 1981-09-11 IT IT23940/81A patent/IT1139974B/en active
-
1982
- 1982-08-30 DE DE8282107970T patent/DE3265425D1/en not_active Expired
- 1982-08-30 AT AT82107970T patent/ATE14884T1/en not_active IP Right Cessation
- 1982-08-30 EP EP82107970A patent/EP0074555B1/en not_active Expired
- 1982-09-01 ZA ZA826408A patent/ZA826408B/en unknown
- 1982-09-02 US US06/414,044 patent/US4558122A/en not_active Expired - Lifetime
- 1982-09-03 IL IL66713A patent/IL66713A/en not_active IP Right Cessation
- 1982-09-06 PT PT75516A patent/PT75516B/en not_active IP Right Cessation
- 1982-09-06 NZ NZ201824A patent/NZ201824A/en unknown
- 1982-09-08 AU AU88135/82A patent/AU564577B2/en not_active Ceased
- 1982-09-09 RO RO108604A patent/RO85286B/en unknown
- 1982-09-09 CA CA000411119A patent/CA1213886A/en not_active Expired
- 1982-09-09 GR GR69247A patent/GR76720B/el unknown
- 1982-09-10 PL PL1982238201A patent/PL141706B1/en unknown
- 1982-09-10 NO NO823088A patent/NO153397C/en unknown
- 1982-09-10 ES ES515613A patent/ES515613A0/en active Granted
- 1982-09-10 HU HU822908A patent/HU186117B/en not_active IP Right Cessation
- 1982-09-10 FI FI823142A patent/FI74290C/en not_active IP Right Cessation
- 1982-09-10 CS CS826560A patent/CS241123B2/en unknown
- 1982-09-10 SU SU823494860A patent/SU1340592A3/en active
- 1982-09-10 JP JP57156930A patent/JPS5857397A/en active Granted
- 1982-09-10 YU YU2046/82A patent/YU43092B/en unknown
- 1982-09-10 DK DK405382A patent/DK149957C/en not_active IP Right Cessation
-
1985
- 1985-08-01 DK DK349085A patent/DK155332C/en not_active IP Right Cessation
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1987
- 1987-02-09 RU SU874028951A patent/RU2041235C1/en active
- 1987-03-23 MX MX567087A patent/MX5670A/en unknown
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